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Designed Beta‐Turn Mimic Based on the Allylic‐Strain Concept: Evaluation of Structural and Biological Features by Incorporation into a Cyclic RGD Peptide (Cyclo(‐ L ‐arginylglycyl‐ L ‐ α ‐aspartyl‐))
Author(s) -
Sukopp Martin,
Marinelli Luciana,
Heller Markus,
Brandl Trixi,
Goodman Simon L.,
Hoffmann Reinhard W.,
Kessler Horst
Publication year - 2002
Publication title -
helvetica chimica acta
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.74
H-Index - 82
eISSN - 1522-2675
pISSN - 0018-019X
DOI - 10.1002/hlca.200290021
Subject(s) - chemistry , moiety , cyclic peptide , stereochemistry , peptide , turn (biochemistry) , allylic rearrangement , residue (chemistry) , amino acid , biochemistry , catalysis
The (3 R ,5 S ,6 E ,8 S ,10 R )‐11‐amino‐3,5,8,10‐tetramethylundec‐6‐enoic acid (ATUA; 1 ), which was designed as a β II′‐turn mimic according to the concepts of allylic strain and 2,4‐dimethylpentane units, was incorporated into a cyclic RGD peptide. The three‐dimensional structure of cyclo(‐RGD‐ATUA‐) (=cyclo(‐Arg‐Gly‐Asp‐ATUA‐)) 4 in H 2 O was determined by NMR techniques, distance geometry calculations and molecular‐dynamics simulations. The RGD sequence of 4 shows high conformational flexibility but some preference for an extended conformation. The structural features of the RGD sequence of 4 were compared with the RGD moiety of cyclo(‐RGDfV‐) (=cyclo(‐Arg‐Gly‐Asp‐ D ‐Phe‐Val‐)). In contrast to cyclo(‐RGDfV‐), which is a highly active α v β 3 antagonist and selective against α IIb β 3, cyclo(‐RGD‐ATUA‐) shows a lower activity and selectivity. The structure of the ATUA residue in the cyclic peptide resembles a β II′‐turn‐like conformation. Its middle part, adjacent to the CC bond, strongly prefers the designed and desired structure.